For the first time, this clinical study was designed using a computational model of human metabolism developed by our laboratory that simulates adaptations of macronutrient metabolism and body composition in response to changes of diet and physical activity (see report 1 Z01 DK013036). Based on our current knowledge of human metabolism, the model allowed us to predict the likely changes of macronutrient metabolism and body composition for various diets, as well as the length of time required to detect those changes given the precision of the experimental measurements. We conducted several simulated clinical studies and selected the protocol design that had the best chance of producing successful results at a reasonable expense and with minimum inconvenience to the study subjects. The computational model will also be used to analyze the data from this study and integrate it within a broader context of our overall understanding of human macronutrient metabolism and regulation of body composition.